Multiple myeloma (MM) is a disease characterized by an excess of malignant plasma cells in the bone marrow (BM). Most MM cells secrete IgG or IgA that contain somatic hypermutations, suggesting that the critical transformation processes occur in the germinal centers and may involve antigenic stimulation. Accumulation and proliferation of malignant myeloma cells result in disruption of normal hematopoiesis and changes to BM vascularization and bone physiology. MM is the second most prevalent hematologic malignancy in the US with a survival rate of 7-8 years when patients are treated with drugs such as proteasome inhibitor bortezomib, or thalidomide and lenalidomide, which target MM cells in the BM microenvironment (Kumar et al. (2008) Blood 111: 2516-2520).
MM is characterized by a wide variety of genetic mutations. Analyses of large numbers of patient MM cells and human myeloma cell lines (HMCLs; Carrasco et al. (2006) Cancer Cell 9: 313-325; Drexler et al. (2000) Leukemia, 14: 777-782; Lombardi et al. (2006) Genes Chromosomes Cancer, 46: 226-238; Moreaux et al. (2011) Haematologica, 96: 574-582) attest to the molecular heterogeneity of this disease. There are two oncogenic pathways that are responsible for the initial onset of MM or the premalignant disease called monoclonal gammopathy of undetermined significance (MGUS)—hyperdiploidy sometimes containing multiple trisomies of chromosomes 3, 5, 7, 9, 11, 15, 19, and 21 and primary immunoglobulin translocations involving 11q13 (CCND1), 4p16 (FGFR3/WHSC1), 6p21 (CCND3), 16q23 (MAF), and 20q11 (MAFB), which result in dysregulated expression of the target genes. Disease progression is marked by activating mutations to K- or N-Ras and inactivation of CDKN2A, CDKN2C, CDKN1B, and/or PTEN tumor suppressor genes. As tumors become more aggressive in later stages of the disease, secondary Ig translocations involving MYC have been found in MM. This is in contrast to human Burkitt's lymphoma and murine plasmacytoma in which c-myc translocation is an early oncogenic event. In addition, mutations and/or deletions of p18 and p53 have been observed as late events in MM pathogenesis.
Interferons have been contemplated for use in the treatment of cancer (Borden et al. (2000) Semin. Cancer Biol., 10: 125-144; Borden et al. (2007) Nat. Rev. Drug Discov., 6: 975-990). There are seven classes of type I IFNs with IFNα and IFNβ being the most abundant. Both IFNα and IFNβ bind to the same receptor composed of two transmembrane proteins, IFNAR 1 and 2, but IFNβ binds with much higher affinity than IFNα (Lamken et al. (2004) J Mol Biol 341: 303-318). IFNs have been shown to have anti-proliferative activity as well as the ability to induce apoptosis in hematological malignancies and solid tumors in addition to their anti-viral activity (as reviewed in Borden et al. (2007) Nat. Rev. Drug Discov., 6: 975-990). However, the effectiveness of IFNα for cancer therapy is overshadowed by side effects when used at high doses (Weiss (1998) Semin. Oncol., 25: 9-13) and by a short half-life of only 1 hour (Peleg-Shulman et al. (2004) J. Med. Chem., 47: 4897-904). Strategies to increase the half-life have included the covalent linkage of polyethylene glycols (PEG) to IFNα (Talpaz et al. (2001) Blood, 98: 1708-1713), but such modifications have resulted in lower activity (Rosendahl et al. (2005) Bioconjug. Chem., 16: 200-207).